It has been established that alterations in body weight both in normal and in obese subjects are accompanied by changes in activity of the autonomic nervous system. This may be important since autonomic function may be an effector arm of alterations in energy metabolism which tend to restore body weight to the "usual" weight after alterations in weight by induced weight loss or weight gain. We employ pharmacological studies of the autonomic control of cardiac function as an estimate of general autonomic activity. Specifically, patients' heart periodicity was measured before and after cardio-selective beta-1 adrenergic blockade and muscarinic cholinergic blockade to obtain estimates of sympathetic control and parasympathetic control. Simultaneously, spectral analysis of heart rate variability is done as a further estimate of these parameters and also to determine the adequacy of blockade. It has been possible to show that there are not only changes in autonomic function when usual weight is varied, but obese individuals at their usual obese weight are different from the non-obese. The obese tend to have lower parasympathetic control and higher sympathetic control. We believe that this makes it unlikely that a primary defect in the autonomic nervous system is responsible for obesity. More likely, the autonomic changes found are simply those that occur when fat mass is increased or decreased by experimental means. We propose to utilize these techniques of evaluating autonomic function in studies of weight response induced not only by caloric alterations but also by the administration of drugs which, in turn, affect energy also metabolism. The degree of alteration in autonomic function in the obese state at usual weight will also be evaluated as a measure which may vary with different genetic factors important in the pathogenesis of obesity. As the molecular genetics of human obesity is better understood, each of the subtypes that emerge will be evaluated for autonomic function.